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Dyslipidemia in Hemodialysis P atients

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Dyslipidemia is empirically defined as plasma lipid and lipoproteins that are associated with adverse outcomes such as CV disease (CVD) in the general population.

Whether this definition is justified in patients with CKD requires further investigations.

J Am SocNephrol18: 1246–1261, 2007. doi: 10.1681/ASN.2006091006

Normal Structure and Function ofLipoproteins

Lipoproteins consist of lipids and proteins (known as apolipoproteins[apo]), with the main function of transporting water- insoluble lipids such as cholesterol or triglycerides in plasma from the sites of absorption (gut) and/or synthesis (liver) to the sites of utilization (peripheral tissues) or processing.

J Am SocNephrol18: 1246–1261, 2007. doi: 10.1681/ASN.2006091006

Besides contributing to the structure and the stability of the macromolecule, Apo lipoproteins control the metabolism of the lipoproteins by activation or inhibition of enzymes and interaction with lipoprotein receptors.

J Am SocNephrol18: 1246–1261, 2007. doi: 10.1681/ASN.2006091006

Pathophysiology of Dyslipidemia in CKDand Dialysis

The spectrum of dyslipidemia in patients with CKD and dialysis patients is distinct from that of the general population.

It involves all lipoprotein classes and shows considerable variations depending on the stage of CKD.

J Am SocNephrol18: 1246–1261, 2007. doi: 10.1681/ASN.2006091006

There seems to be a gradual shift to the uremic lipid profile as kidney function deteriorates.

Apart from quantitative differences, major qualitative changes in lipoproteins can be observed, such as oxidization and modification to sdLDL, which render the particles more atherogenic.

J Am SocNephrol18: 1246–1261, 2007. doi: 10.1681/ASN.2006091006

Hypertriglyceridemia

Plasma triglycerides are predominantly found in two types of lipoproteins in normal individuals.

These are chylomicrons, which are assembled in the intestine for the transport of dietary fatty acids, and VLDL, which are produced in the liver for the transport of endogenous fatty acids.

J Am SocNephrol18: 1246–1261, 2007. doi: 10.1681/ASN.2006091006

The accumulation of triglycerides is the consequence of both a high production rate and a low fractional catabolic rate .

The reduced fractional catabolic rate is likely due to the decreased activity of two endothelium-associated lipases, namely, LPL and hepatic triglyceride lipase, which have the primary physiologic function of cleaving triglycerides into FFA for energy production or storage.

J Am SocNephrol18: 1246–1261, 2007. doi: 10.1681/ASN.2006091006

The cause of the decreased lipase activities in uremia is thought to be depletion of the enzyme pool induced by frequent heparinization in hemodialysis (HD) patients

An increase in the plasma apoC-III/apoC-II ratio, and the presence of other lipase inhibitors in plasma.

ApoC-II is an activator of LPL, whereas apoC-III is an inhibitor of LPL.

J Am SocNephrol18: 1246–1261, 2007. doi: 10.1681/ASN.2006091006

The increased apoC-III/apoC-II ratio is usually due to a disproportionate increase in plasma apoC-III .

The impaired lipase activities in uremic plasma may also be caused by a decrease in LPL synthesis as a result of secondary hyperparathyroidism or suppressed insulin level .

J Am SocNephrol18: 1246–1261, 2007. doi: 10.1681/ASN.2006091006

High-Density Lipoprotein

Patients with CKD generally have reduced plasma HDL cholesterol concentrations compared with nonuremicindividuals Because of the low apo-AI level and decreased LCAT activity , the esterification of free cholesterol and hence the conversion of HDL3 to HDL2 are diminished in uremia.

Observational Studies ofHypercholesterolemia in the DialysisPopulation

The coronary risk factors for individuals with stage 1 or 2 CKD are generally quite similar to those without kidney disease .

Clin J Am SocNephrol4: S95–S101, 2009. doi: 10.2215/CJN.04780709

In contrast, a number of epidemiologic studies and a few randomized clinical trials have shown unconventional associations of cardiovascular risk factors with clinical outcomes in long-term dialysis patients.

The first large observational study relating serum cholesterol levels and clinical outcomes was published in the early 1990s, based on the database of National Medical .

Lowrie EG, Lew NL: Death risk in hemodialysis patients:

The predictive value of commonly measured variables and

an evaluation of death rate differences between facilities.

Am J Kidney Dis 15: 458–482, 1990

In that study, a U-shape relationship between serum total cholesterol level and the risk for all-cause mortality was observed, with the lowest risk found in the category with cholesterol levels between 200 and 250 mg/dl.

Cholesterol levels between 250 and 300 mg/dl seemed to be associated with a modest increase in mortality risk, but the subgroup with cholesterol levels 100 mg/dl had a three-fold increase in mortality risk after adjustment for case mix.

Lowrie EG, Lew NL: Death risk in hemodialysis patients:

The predictive value of commonly measured variables and

an evaluation of death rate differences between facilities.

Am J Kidney Dis 15: 458–482, 1990

(CHOICE) Study by Liu et al. is compatible with this hypothesis.

In that analysis, 823 incident dialysis patients were classified by the presence or absence of inflammation and/or malnutrition (defined as low serum albumin levels or elevated serum levels of C-reactive protein or IL-6).

An increase in baseline serum cholesterol level was associated with a decreased risk for all-cause mortality in the entire CHOICE cohort.

Theprimary end point was a composite of death from cardiac causes, nonfatal myocardial infarction, and stroke.

Secondary end points included death from all causes and all cardiac and cerebrovascular events combined.

Die Deutsche Diabetes Dialyse Studie (4D) targeted German

patients who had type 2 diabetes and ESRD and were on

long-term hemodialysis

There are several potential interpretations of this seemingly negative result.

First, LDL cholesterol may not be important in the pathogenesis of cardiovascular disease in dialysis patients.

Second it could mean that atherosclerosis is not a major cause of cardiovascular death.

The most common causes of cardiac death listed in the US Renal Data System and the Hemodialysis (HEMO) Study were sudden death, arrhythmia, and unknown.

Die Deutsche Diabetes Dialyse Studie (4D) targeted German

patients who had type 2 diabetes and ESRD and were on

long-term hemodialysis

A third potential explanation is that statins are, in fact, effective in decreasing cardiovascular events in dialysis patients with diabetes, but the sample size of the 4D Study was not sufficiently large to detect the modest effect.

Die Deutsche Diabetes Dialyse Studie (4D) targeted German

patients who had type 2 diabetes and ESRD and were on

long-term hemodialysis

A post hoc analysis was conducted of the 4D (Die Deutsche Diabetes Dialyze) study to investigate whether LDL-cholesterol at baseline is predictive of cardiovascular events and whether the effect of atorvastatin on clinical outcomes depends on LDL-cholesterol at baseline.

In patients with type 2 diabetes mellitus undergoing hemodialysis, atorvastatin significantly reduces the risk of fatal and nonfatal cardiac events and death from any cause if pretreatment LDL-cholesterol is 145 mg/dl (3.76 mmol/L).

Die Deutsche Diabetes Dialyse Studie (4D) targeted German

patients who had type 2 diabetes and ESRD and were on

long-term hemodialysis

A study to evaluate the Use of Rosuvastatin in subjects On Regular hemodialysis: an

In this study, 9270 patients with CKD with no history of myocardial infarction or coronary revascularization were randomized to simvastatin/ ezetimibeor placebo.

The study included 3023 patients undergoing dialysis at study entry, and 2000 additional patients reached ESRD during the course of the study.

The intervention resulted in a net decrease in LDL cholesterol of 35 mg/dl, and over a median follow-up of 4.9 years, a 17% lower risk for atherosclerotic vascular events (nonfatal myocardial infarction, coronary death, ischemic stroke, arterial revascularization)

There was no reduction in either overall or cardiovascular mortality.

Only one-quarter of all vascular deaths were classified as being secondary to atherosclerosis .

Recommendation

In the dialysis population, approximately 60 percent of all cardiac deaths are presumably due to sudden death or arrhythmias.

We agree with the 2013 KDIGO guidelines that suggest that statin therapy be continued in patients who are already receiving statins or a statin/ezetimibe combination at the time of initiation of dialysis.

if statin therapy is administered to dialysis patients, the following goals are reasonable, although they have not been validated in dialysis patients: